Efficient Early Clinical Research to Achieve Clinical Proof-of-Concept Requires Patients
J. Fred Pritchard PhD Vice President, Global Drug Development
Questions
2
What are the latest measures of efficiency in drug development?
How is early clinical research changing? What are some ways of making first-in-human
studies more informative and efficient? What are some challenges and strategies for
engaging patients in early clinical studies? What innovations are making early clinical
research more efficient and effective? What are some challenges in conducting
complex early clinical studies in patients? Is there globe warming to early clinical
research?
New Drug And Biologics Approvals/R&D Spending
Reprinted with Permission: Tufts CSDD: PhRMA 2014 industry Profile
Phase Transition Rates
Tufts CDSS 2014 Hays 2014
Reprinted with Permission: Tufts CSDD: PhRMA 2014 industry Profile
Changing Paradigm
Source: William Blair & Company, (Bain and Company) Covance Investors Overview June 16, 2010
Learn Confirm Decide
Translational Medicine
Regional and Ethnic Differences
Searching for More Efficient Ways of Managing Risk in Drug Development
Engineered Process Stepwise Early studies structured same as later studies –
primary objectives and endpoints Influenced by “rules-based” regulations
Preclinical
Phase I: safety, tolerance, PK (healthy participants)
Phase II: dose response (small groups of patients)
Phase III: safety and efficacy (statistically robust)
Phase IV: post-approval surveillance
Global filings to each market
Filings for new indications
Adaptive Development Feedback loops to discovery (Translational
Medicine) Early studies fused with multiple objectives and
endpoints Influenced by emerging “risk-based”guidances Learn Preclinical
Human Microdose - PK Early Clinical: safety, tolerance, PK (healthy
subjects and patients) Proof-of-Presence Proof-of-Mechanism Proof-of-Concept
Dose Response Confirm:
Safety and efficacy (statistically robust) Uptake:
Simultaneous global filings Post-approval surveillance Filings of new indications
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What’s Driving Evolution of New Paradigm?
Increase in novel new drugs from
discovery research
Greater regulatory expectations on
clinical trials
Increased cost of clinical research
More difficult disease states to study and treat
Expanding universe of new
technology applications
Need for more informed decisions at clinical Proof-of-
Concept
Regulatory acceptance of
adaptive-like study designs
Innovation
Clinical Proof-of-Concept is where a
new drug acquires real value
Attrition Rate of NME Due to PK/ADME
0
5
10
15
20
25
30
35
40
45
% Attrition Rate
1964-19852000
J. Clin. Pharmacol. 1988 Nat. Rev. Drug Disc. 2004
NME: New Molecular Entity PK: Pharmacokinetic ADME: Absorption, Distribution, Metabolism & Excretion
Characteristics of an Efficient First-in-Human Study
Establishes drug does not elicit acute, treatment-limiting adverse events
Characterizes the ADME properties: Peak exposure Overall exposure Half-life
Identifies influences for future patient exposure Effect of food for oral dosing Site of administration for Subcutaneous (SC) Timing of dose
Minimizes time and cost to Proof-of-Concept (POC) step
Efficient First-in-Human Designs
SAD HS – 1st dose level
SAD HS – 2nd dose level
SAD HS – 3rd dose level
SAD HS – 4th dose level
MAD HS – 1st dose level SAD HS – 5th dose level
MAD HS – 2nd dose level
MAD HS – 3rd dose level
MAD HS – 4th dose level
MAD HS – 5th dose level
SAD HS = Single Ascending Dose – Healthy Subjects
MAD HS = Multiple Ascending Dose – Healthy Subjects
Tim
e
Simulate exposure using non-compartmental or compartmental approach
What Do We Know/Understand Regarding the Target Population?
Will it be likely the POC population
will be on conmeds known to
perpetrate DDIs?
Indicated in obese
patients? Is meal time important?
CYP1A Substrate,
will smokers receive drug
in POC?
CYP: Cytochrome P450 Enzyme POC: Proof-of-Concept DDI: Drug-Drug Interaction
Integrate Intrinsic/Extrinsic Factors into SAD/MAD
SAD HS – 1st dose level
SAD HS – 2nd dose level
SAD HS – 3rd dose level
SAD HS – 4th dose level
MAD HS – 1st dose level SAD HS – 5th dose level
MAD HS – 2nd dose level
MAD HS – 3rd dose level
MAD HS – 4th dose level
MAD HS – 5th dose level
Tim
e
Simulate exposure using non-compartmental or compartmental approach
Patient population?
X-Over Food Effect
Intrinsic factors (e.g. obese, elderly?)
Extrinsic factor (e.g. smoking, DDI)
Integrate Intensive Electrocardiographic (ECG) Monitoring for Early Cardiovascular Signal
SAD HS – 1st dose level
SAD HS – 2nd dose level
SAD HS – 3rd dose level
SAD HS – 4th dose level
SAD HS – 5th dose level
Tim
e
Each Cohort ECG Extractions Single 24hr Holter
monitoring session Three triplicate
baseline timepoints 6-9 triplicate post-
dose timepoints Proactively plan for
extended supine periods
SAD Allows for Evaluation of Potentially Supra-Therapeutic Exposure
Concentration (ng/ml) QTcF: Fridericia corrected QT interval msec: millisecond Δ: Greek letter ‘Delta’ represents change from baseline, change from placebo
Important “Proofs” in Early Clinical Research
Proof-of-Presence Does the drug get to its site of
action? Value Add: $
Proof-of-Mechanism Does the drug affect the
biological target as it was designed?
Value Add: $$$
Proof-of-Concept Is there a sufficient signal that
the drug favorably impacts the disease with acceptable risk of toxicity that would stimulate further investment in the drug?
Value Add: $$$$$
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Pharmacokinetics Tissue concentrations Healthy subjects (HS) or
patients
Biomarkers reflecting target engagement
Biomarkers of toxicity (liver, kidney effects)
Healthy subjects or patients
Biomarkers reflecting impact on disease
Biomarkers of toxicity (liver, kidney effects)
Patients
Early Signals of Clinical Safety and Efficacy are the Key to Applied Translational Medicine
To get an early sense that a drug is working in humans as it was designed, you need:
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Patients • Small number • Stable disease • Minimal confounding
treatments • Appropriately motivated
Investigators / Clinical Trial Units • Small number of sites • Scientifically / medically robust • Controlled study setting • Follow global GCP standards • Ethical
Access to Patient/Special Populations and Specialists
Special Populations Renal Impairment Hepatic Impairment Elderly Women Pediatric/Adolescent
Patient Populations Diabetes Mellitus Asthma Chronic Obstructive Pulmonary
Disease (COPD) Rheumatoid Arthritis Systemic Lupus Erythematosus (SLE) Psoriasis Alzheimer’s Disease Schizophrenia Depression Cancer Hypertension Hyperlipidaemia Infectious Diseases
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The Challenge of Recruiting Patients to Early Clinical Studies
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Benefit to the Patient
Otherwise Healthy Patient
Disease Prevalence
Alternative Treatments
Withdrawal from current treatment
Number and type of co-medications
Gender, age, race and ethnicity
Single disease
Usually no drug benefit - Not dosed long enough - Optimal dosing not established
Financial compensation - Sometimes allowed like HS studies
Can negatively impact health insurance coverage for their disease
Risks to patient unknown
Appeal to altruism
Early Clinical Research Requires Resources Dedicated to Research
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Heparinized blood
Urine
Non-coagulated blood
Lab C – LC/MS/MS assay pathophysiological substrate and product
WBCs
Lab D Pharmacogenomic
assay
Serum
Lab B Clinical chemistry
Tissue Biopsy
Lab F Stimulated cell assay
Lab G Future
proteomics
Lab E Target
enzyme assays
Lab B Urinalysis
Add stabilizer
Add stabilizer
Freeze
Lab A
LC-MS/MS assay parent drug and
metabolites
Freeze Plasma
Complex sample collection schedules and processing procedures
Example: First-in-Patient study – 14 tests, 7 labs
A Perfect Scenario for Fast-to-Patient Strategy
Sequence Patients Treatment Periods
P1 P2 P3
1 2 3
N = 5 N = 5 N = 5
PLA 25 mg 25 mg
75 mg PLA
75 mg
200 mg 200 mg
PLA
Sequence Patients Treatment Periods
P’1 P’2 P’3
4 5 6
N = 5 N = 5 N = 5
PLA 50 mg 50 mg
100 mg PLA
100 mg
300 mg 300 mg
PLA
Single Ascending Dose (SAD) Study Novel Dipeptidyl Peptidase-4 (DPP4) Inhibitor in Mild
Diabetic Patients No other drugs
Time (h)
0 1 2 4 6 12 24
AM
G 2
22 C
once
ntra
tions
(ng/
mL)
0123456789
1011121314151617181920
Lower limit of quantitation
25 mg 50 mg 75 mg 100 mg 200 mg 300 mg Placebo
Time (h)
0 1 2 4 6 12 24
AM
G 2
22 C
once
ntra
tions
(ng/
mL)
0.01
0.1
1
10
100
Lower limit of quantitation
25 mg 50 mg 75 mg 100 mg 200 mg 300 mg Placebo
Results of SAD Study in Mild Diabetic Patients: Early Evidence of Efficacy
Time (h)
0 1 2 4 5 6 11 12 24 25 26
Glu
cose
Con
cent
ratio
ns (m
g/dL
)
6080
100120140160180200220240260280300320340360380400 25 mg
50 mg 75 mg 100 mg 200 mg 300 mg Placebo
Time (h)
0 1 2 4 5 6 11 12 24 25 26
GLP
-1 C
once
ntra
tions
(pM
)
-5
0
5
10
15
20
25
30
35
40
45
50
Lower limit of quantitation
25 mg 50 mg 75 mg 100 mg 200 mg 300 mg Placebo
Time (h)
0 1 2 4 6 12 24
Per
cent
(%) I
nhib
ition
in D
PP
-IV A
ctiv
ity
0
10
20
30
40
50
60
70
80
90
100
110 25 mg50 mg 75 mg 100 mg 200 mg 300 mg Placebo
X
Drug Plasma Concentration Percent DPP4 Inhibition
Glucagon-Like Peptide-1 Concentration Glucose Concentration
F=4-8%
Good
Activity
Innovations in Early Clinical Research
New Biomarkers of drug action and effect Imaging (SPECT, functional MRI/PET), microRNAs, tracking genetic
changes in tumors or microbiome, digital high resolution EEGs and ECGs Patient Recruitment
Social media tools to recruit patients Electronic patient records to quickly assess impact of I/E criteria on
recruitment and suitability of patients for a study Data Acquisition
Digital capture of data – real-time review and monitoring for quality Video for remote viewing of study conduct in real time Tablets and smart phones to capture patient data Electronic tracking to confirm study compliance
Data Analysis Data repositories that allow comparison across studies and advanced
modelling to predict drug response in specific patient settings
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Global Clinical Pharmacology Unit Networks
Most patient needs in early clinical research cannot be met by a single center
Increasing the number of sites has its own challenges Need to evolve similar partnering and alliance models among
groups of clinical pharmacology units Work to same quality standards (undergo common systems
Quality Assurance audits) Coordinated through a group which also brings in other study
services as protocol preparation, bioanalysis, pharmacokinetics, data management and statistics, clinical study report preparation
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Examples of networks and therapeutic clusters
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Patient Population Celerion Site
External Site Network
Diabetes / Obesity Phoenix Lincoln
Supporting networks in North America (NA), Europe, South Korea and Singapore
Respiratory and Inflammatory (asthma, COPD, cystic fibrosis)
Belfast Strong network in UK and Germany (therapeutic cluster) Current US study at Temple Lung Center
Ophthalmology Belfast Phoenix
Strong network in UK and Germany (therapeutic cluster)
Cardiovascular (hypertension, hypercholesterolemia, hyperlipidemia, thrombosis)
Belfast Phoenix
Strong networks in Europe and Korea (therapeutic cluster)
Oncology (blood, breast, colon, prostate, lung, pancreatic, ovarian, skin)
Strong networks in Korea (therapeutic cluster) Good access in Europe Major academic cancer centers dominate NA
Renal or Hepatic Insufficiency Strong network in US and Europe
Rheumatoid Diseases (RA, OA, SLE) Belfast Strong networks in Korea and in Europe (therapeutic cluster)
CNS /Neurology (Alzheimer’s, schizophrenia, anxiety, depression, pain, Parkinson’s, convulsion)
Collaborative neuroscience network in US Good access in Europe and Korea
Infectious Disease (HIV, HCV, HSV, influenza, bacterial)
HCV – Europe and Korean sites (Asian phenotypes), Influenza/bacterial: access in Europe and Korea
Reasons for Performing Clinical Pharmacology Studies in Asia-Pacific Region
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1. Access to patients for early clinical assessment of safety, PK and signals of efficacy and dose response
2. Bridging PK and PK/PD studies to support registrations of drug products in Asian markets
3. Support First-in-Human assessments of drugs discovered and developed in Korea, Singapore, China, Japan and other Asian nations
Market Drivers
Operational Factors 1. Modern, well equipped clinical trial centers at major medical centers with ready
access to many patient populations 2. Some regulatory environments similar to North America and Europe 3. Well-trained scientific and medical staff that can communicate in English
Needs 1. Pharma companies need studies to support products for Asian markets 2. Asian clinical trial centers need access to global pharma study opportunities and
best operating practices for running efficient operations
Regulatory Environment in Five Asia/Pacific Countries
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Japan China South Korea
Singapore Australia
Regulatory Review Time
No queries – 30 days after CTN submission
11 Months 30-60 Days 15-30 Days No approval for healthy subject studies
Ethics / IRB Review Time
Variable 60 Days 2-4 Weeks 1-4 Weeks 12-16 Weeks (patients)
Parallel or Sequential Parallel Sequential Parallel Parallel Clinical Trial Notification acknowledged in days
Clinical Trial Centers Hospital and CRO-owned
SFDC-accredited CTCs
15 Hospital-based CTCs
1 Pharma-owned and 3 Hospital CTCs
5 Academic hospital clinics
Other Comments Government funding new CTCs
Difficult to ship samples out of China
MFDS built on US FDA model
Translational medicine focus
Less CMC and preclinical safety
Audit Results of 7 Asian CTCs 2013-2014
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1 2 3 4 5 6 7Phase 1 CTC (facilities)Clinical Processing/Sample ManagementStudy Set Up, Execution, LogisticsPI OversightIRBPharmacy (including Security)Data ManagementQuality Control (inc. Documents)Equipment (Calibration, Maintenance)Computer System ValidationInformation TechnologyArchives / Document Storage (Security)CTC Facility and SecurityBCP/DCP and TestingQuality Systems (SOPs & Policies)Controlled Document ProcessQuality Assurance (QA/QI)CAPA ProcessCTC Organizational ChartStaff Qualification Records (CVs, JDs)Staff Training and RecordsVendor ManagementRegulatory Inspection HistoryAccreditations
Inadquate or missingWork needed to pass global auditSome changes needed to pass global auditAcceptable for global audit
Quality
Most sites never had a full systems audit against global standards/ expectations
Variability across sites in areas of strength and weakness Strengths: Across all sites were Phase I CTC facility and
Security, Principal Investigator (PI) Oversight and Institutional Review Board (IRB) or Ethics Committee.
Weaknesses: Staff Qualification records (6 of 7 sites), IT and Computer System Validation (4 of 7 sites), QA (4 of 7 sites), Vendor Management (4 of 7 sites), Staff Training Records (4 of 7 sites), Pharmacy (3 of 7 sites) and CAPA process (3 of 7 sites)
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Five Key Elements of Clinical Success in Applying Translational Medicine
Expertise: Scientific and medical staff with the portfolio of skills to design, conduct and interpret complex clinical studies
Experience: Leveraging knowledge gained from conducting early clinical pharmacology studies with high density sampling
Facilities and Equipment: Modern confinement clinics and laboratories equipped with innovative technologies to meet the varying and evolving demands of early clinical research
Access to Patients: Recruiting the right participant or patient to meet the needs of specific study designs in a timely and ethical way.
Access to Biomarkers: Leveraging capabilities resident within the participating clinics or laboratories or with qualified vendor labs to create the appropriate palate of tests to ascertain the drug’s effect in humans
Bridging Strategy
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Start design of CPoC study first What is “Proof”? Endpoints? What patients? How many? How to get to CPoC? What can I do in healthy participants? Are biomarkers available? Develop novel biomarkers?
Biochemical assays Imaging and imaging agents MicroRNA panels
Would microtracer studies be valuable? Can PK/PD modeling be applied? What preclinical work is needed to support the early clinical program?
The Three Constraints
Brief Answers to Questions
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Latest metrics of efficiency in clinical research 10-15% of drugs entering clinical trials make it to market
How is early clinical research changing? Focus on Clinical Proof-of-Concept – fail early
How are traditional FIH studies changing? Fusion studies answering multiple questions on safety, PK, DDIs
What are some challenges and strategies for engaging patients in early early clinical studies? Patient benefits vs risk Regional differences, patient networks
What are some challenges in conducting early clinical research studies in patients? Access to biomarkers, specialty equipment and specialist researchers Sample logistics
What innovations are making early clinical research more efficient and effective? Digital communications, real-time acquisition and access to data, apply complex analysis
and modeling, new biomarkers
Why is there increasing attention to Asia-Pacific region in early clinical research? Access to patients, modern clinical trial centers, educated staff, rapidly emerging
biotechnology industry, large market